1. Field of the Invention
The invention relates to stable topical formulations with good active ingredient release characteristics, containing at least one macrolide antibiotic which is stabilized with at least one former of oppositely charged ions which has one or more linear and/or branched alkyl substituents.
2. Discussion of the Background
Macrolide antibiotics such as erythromycin belong to the group of drugs which are not well absorbed, because of their hydrophilic structural elements (Langguth, P. and Mutschler, E., 1987, Arzneim.-Forsch., 37 II, 12:1362-1366).
Bojarska-Dahlig, H., et al. (1981, "Curr. Chemother. Immunother. Proc. Int. Congr. Chemother.", 12th Meeting, Ed. Periti, P., and Gialdroni-Grassi, G., Am. Soc. Microbiol., Wash. D.C., Vol. 2. pp. 898-900) describe the lipophilization of erythromycin and erythromycin derivatives with 1,3-dioxolan-2-one units, and the resulting increase in antibacterial potency of erythromycin derivatives. The effect of newly introduced substituents on the stiffness and surface characteristics of the erythromycin molecule, and the influence of these parameters on the formation of ribosomal complexes in microorganisms, are discussed.
Eur. Pat. 0,426,029 (U.S. Ser. No. 89/428,803) describes a method of reduction of the lipophilicity of erythromycin and 6-0-methyl-erythromycin by incorporation of, e.q., substances in micelles which are comprised of steroids such as cholates, desoxycholates, glycocholates, etc. The result is injectable emulsions by means of which macrolide antibiotics may be administered intravenously.
In Jap. Pat. App. 62-029,511 (Eur. OS 211,250), lipophilic emulsions of erythromycin bases in an aqueous solution of a phosphatide are described which are produced under pressure by addition of additional emulsifiers. The lipophilic particles in the aqueous matrix have a mean diameter c. 0.1 micron.
PCT OS 90/08,537 describes formulations for oral administration of pharmaceutical compounds which comprise a therapeutically effective amount of a drug, further an organic solvent, an oil, and, optionally, lipophilic oppositely charged ions, stabilizers, and emulsifiers. The formulations contain, among other things, poorly absorbable antibiotics such as erythromycin, doxorubicin, gentamycin, or tosufloxacin. The oral availability of the erythromycin base is twice that provided by the customary tablet formulations.
Eur. Pat. 43,738 (=U.S. Pat. No. 4,954,487) relates to formulations for topical administration of pharmaceutical compounds which formulations comprise a medium for the transport of the drug through the intact skin, which medium is comprised of:
(1) Diols with 3-4 C atoms, diol esters, or diol ethers; and PA1 (2) Cell wall perturbing substances such as alkenols, alkenylcarboxylic acids, fatty acids, and glycerides. PA1 Reduction of the lipophilicity of macrolide antibiotics (Eur. OS 0,426,029); or PA1 Increase of the lipophilicity, as is desired for topical application.
A formulation for topical application containing erythromycin showed improved skin penetration, and thereby proved effective as a drug for combating acne and other systemic disorders.
Currently commercially available preparations for topical application of macrolide antibiotics, particularly erythromycin preparations, have low release and stability of the active ingredient, and have high concentrations of volatile alcohols, e.g. ethanol or 2-propanol, whereby the volatility results in changes in the effectiveness and consistency of the preparation.
The publications of the state of the art concern
The method of lipophilization of erythromycin or its derivatives described by Bojarska-Dahlig et al., loc.cit., is expensive, starting with the expensive synthesis employed and therebeyond, and is intended for oral administration with high blood absorptivity and high resistance of the antibiotic to gastric juice.
The lipophilic emulsions claimed in Jap. Pat. App. 62/029,511 are administered parenterally and thus are unsuitable for topical application, as are the oral formulations in gelatin capsules claimed in PCT OS 90/08537, which contain oil, organic solvents, and other additives in addition to the active principle (erythromycin).
The formulations for topical administration of drugs which formulations are described in Eur. Pat. 43,738 contain, e.q., erythromycin as the active ingredient, and diols or diol derivatives, and alkenols and alkenol derivatives, as additives. These costly formulations contain a certain proportion of volatile substances which lead to the above-described problems concerning stability over time.
Accordingly, a need continues to exist for lipophilized macrolide antibiotics, and/or formulations containing macrolide antibiotics, for topical administration which exhibit good active principle release characteristics.